The present invention relates to pyrimidine, triazine and pyrazine derivatives of the formula 
Compounds of formula I are metabotropic glutamate (mGluR 1) receptor antagonists and are useful in the treatment of disorders responsive to mediation of the mGluR 1 receptors, such as acute and/or chronic neurological disorders
In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor.
L-glutamic acid, the most commonly occurring neurotransmitter in the CNS, plays a critical role in a large number of physiological processes. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group forms ligand-controlled ion channels. The metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein-coupled receptors.
At present, eight different members of these mGluRs are known and of these some even have sub-types. On the basis of structural parameters, the different second messenger signaling pathways and the different affinity to low-molecular weight chemical compounds, these eight receptors can be sub-divided into three sub-groups: mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.
Ligands of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as epilepsy, stroke, chronic and acute pain, psychosis, schizophrenia, Alzheimer""s disease, cognitive disorders and memory deficits.
Other treatable indications in this connection are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are Huntington""s chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depression
The present invention is a compound of formula 
or a pharmaceutically acceptable salt thereof wherein
R1 is selected from the group consisting of nitro and cyano;
R2 is selected from the group consisting of hydrogen, (C1-C7)-alkyl and xe2x80x94NHR10, and wherein
R10 is selected from the group consisting of hydrogen, (C1-C7)-alkyl, xe2x80x94(CH2)mxe2x80x94OR11, xe2x80x94(CH2)pxe2x80x94(C3-C6)-cycloalkyl, xe2x80x94(CH2)mxe2x80x94NHxe2x80x94C(O)Oxe2x80x94(C1-C7)-alkyl, and xe2x80x94(CH2)p-pyridyl and R11 is selected from the group consisting of hydrogen and (C1-C7)-alkyl;
R3 is selected from the group consisting of hydrogen, (C1-C7)-alkyl, fluoro, hydroxy, (C1-C7)-alkoxy, (C1-C7)-alkylthio, cyano and nitro;
R4 is selected from the group consisting of hydrogen and fluoro; 
xe2x80x83is selected from the group consisting of 
R5 is selected from the group consisting of hydrogen, (C1-C7)-alkyl, (C1-C7)-alkenyl, xe2x80x94(CH2)mxe2x80x94OR11, fluoro-(C1-C7)-alkyl and xe2x80x94(CH2)nCN;
R6 is selected from the group consisting of (C1-C7)-alkyl, halogen, hydroxy, (C1-C7)-alkoxy, (C1-C7)-alkylthio, xe2x80x94Oxe2x80x94(CH2)mxe2x80x94OR11, xe2x80x94O-fluoro-(C1-C7)-alkyl and xe2x80x94NHR12, and
R12 is selected from the group consisting of (C1-C7)-alkyl, xe2x80x94(CH2)mxe2x80x94OR11, xe2x80x94(CH2)pxe2x80x94(C3-C6)-cycloalkyl and xe2x80x94(CH2)p-pyridyl;
R7 is selected from the group consisting of hydrogen, (C1-C7)-alkyl and phenyl;
R8 is selected from the group consisting of hydrogen, (C1-C7)-alkyl and phenyl;
Z is selected from the group consisting of 
R9 is selected from the group consisting of hydrogen, hydroxy and cyano;
m is independently from each other in each occurrence 2, 3, 4, 5 or 6;
n is independently from each other in each occurrence 1, 2, 3, 4, 5 or 6; and
p is independently from each other in each occurrence 0, 1, 2, 3, 4, 5 or 6.
It has now been found that the compounds of formula I are antagonists of the metabotropic glutamate receptor.
Objects of the present invention are compounds of formula I or pharmaceutically acceptable salts thereof and their use as pharmaceutically active substances. Methods for the preparation of the above mentioned substances and pharmaceutical compositions based on compounds of formula I and their production are also objects of the present invention. The invention also is a method of treatment of conditions responsive to mediation of group I mGluR receptors comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a person in need of such treatment.
A preferred compound of formula I within the scope of the present invention has the formula 
or a pharmaceutically acceptable salt thereof, wherein
R1 is selected from the group nitro and cyano;
R2 is selected from the group consisting of hydrogen, (C1-C7)-alkyl and xe2x80x94NHR10, and wherein R10 is selected from the group consisting of hydrogen, (C1-C7)-alkyl, xe2x80x94(CH2)mxe2x80x94OR11, xe2x80x94(CH2)pxe2x80x94(C3-C6)-cycloalkyl, xe2x80x94(CH2)mxe2x80x94NHxe2x80x94C(O)Oxe2x80x94(C1-C7)-alkyl and xe2x80x94(CH2)p-pyridyl; wherein R11 is hydrogen or (C1-C7)-alkyl;
R3 is selected from the group consisting of hydrogen, (C1-C7)-alkyl, fluoro, hydroxy, (C1-C7)-alkoxy, (C1-C7)-alkylthio, cyano and nitro;
R4 is hydrogen or fluoro;
R5 is selected from the group consisting of hydrogen, (C1-C7)-alkyl, (C1-C7)-alkenyl, xe2x80x94(CH2)mxe2x80x94OR11, fluoro-(C1-C7)-alkyl and xe2x80x94(CH2)nxe2x80x94CN;
Z is selected from the group consisting of 
R9 is selected from the group consisting of hydrogen, hydroxy and cyano;
m is independently from each other in each occurrence 2, 3, 4, 5 or 6;
n is independently from each other in each occurrence 1, 2, 3, 4, 5 or 6; and
p is independently from each other in each occurrence 0, 1, 2, 3, 4, 5 or 6.
A further preferred compound of formula Ia has the formula 
wherein R2 is lower alkyl and R5 is selected from the group consisting of (C1-C7)-alkyl, (C1-C7)-alkyl subsituted by halo and (C1-C7)-alkyl substituted by hydroxyl.
A preferred compound of formula Ia1 is selected from the group consisting of 6-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-3-(2,2,2-trifluoro-ethyl)-3H-pyrimidin-4-one;
3-ethyl-6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one; and
6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-3-(2-hydroxy-ethyl)-2-methyl-5-nitro-3H-pyrimidin-4-one.
Another preferred compound of formula Ia has the formula 
wherein R2 is selected from the group consisting of (C1-C7)-alkyl and xe2x80x94NHR10, wherein R10 is selected from the group consisting of (C1-C7)-alkyl, xe2x80x94(CH2)mxe2x80x94OR11, xe2x80x94(CH2)pxe2x80x94(C3-C6)-cycloalkyl, and R11 is selected from the group consisting of hydrogen and (C1-C7)-alkyl, xe2x80x94(CH2)mxe2x80x94NHxe2x80x94C(O)Oxe2x80x94(C1-C7)-alkyl and xe2x80x94(CH2)p-pyridyl;
R3 is selected from the group consisting of hydrogen and fluoro; and
wherein R9 is hydrogen.
A more preferred compound of formula Ia2 is wherein R3 is hydrogen and R5 is selected from the group consisting of (C1-C7)-alkyl, xe2x80x94(CH2)mxe2x80x94OR11 and fluoro-(C1-C7)-alkyl.
An exemplary more preferred compound of formula Ia2 is selected from the group consisting of 6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-3-(2,2,2-trifluoro-ethyl)-3H-pyrimidin-4-one, 2-methyl-5-nitro-6-(4-phenyl-piperidin-1-yl)-3-(2,2,2-trifluoro-ethyl)-3H-pyrimidin-4-one, and 6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-3-(2-methoxy-ethyl)-2-methyl-5-nitro-3H-pyrimidin-4-one.
An additional preferred compound of formula I has the formula 
or a pharmaceutically acceptable salt thereof.
A further preferred compound of formula Ib has the formula 
wherein
R2 is selected from the group consisting of (C1-C7)-alkyl and xe2x80x94NHR10; and
R10 is selected from the group consisting of (C1-C7)-alkyl, xe2x80x94(CH2)mxe2x80x94OR11, xe2x80x94(CH2)pxe2x80x94(C3-C6)-cycloalkyl, and R11 is selected from the group consisting of hydrogen, (C1-C7)-alkyl, xe2x80x94(CH2)mxe2x80x94NHxe2x80x94C(O)Oxe2x80x94(C1-C7)-alkyl and xe2x80x94(CH2)p-pyridyl;
R3 is selected from the group consisting of hydrogen and fluoro;
R6 is selected from the group consisting of halogen, (C1-C7)-alkoxy, (C1-C7)-alkylthio, xe2x80x94Oxe2x80x94(CH2)mxe2x80x94OR11, xe2x80x94O-fluoro-(C1-C7)-alkyl and xe2x80x94NHR12; and
R12 is selected from the group consisting of (C1-C7)-alkyl, xe2x80x94(CH2)mxe2x80x94OR and xe2x80x94(CH2)pxe2x80x94(C3-C6)-cycloalkyl.
An exemplary preferred compound of formula Ib1 is selected from the group consisting of 2-(cyclopropylmethyl-amino)-4-[4-(4-fluoro-phenyl)-piperazin-1-yl]-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile, 2-(cyclopropylmethyl-amino)-4-(2-hydroxy-ethylamino)-6-(4-phenyl-piperazin-1-yl)-pyrimidine-5-carbonitrile, 2-caclopropylamino-4-[4-(4-fluoro-phenyl)-piperazin-1-yl]-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile, 2-caclopropylamino-4-(2-hydroxy-ethylamino)-6-(4-phenyl-piperazin-1-yl)-pyrimidine-5-carbonitrile, 2-{6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-pyrimidin-4-yloxy}-ethanol, and 2,4-bis-cyclopropylamino-6-(4-phenyl-piperazin-1-yl)-pyrimidine-5-carbonitrile.
An additional preferred compound of formula Ib has the formula 
wherein
R2 is selected from the group consisting of (C1-C7)-alkyl and xe2x80x94NHR10,
R10 is selected from the group consisting of (C1-C7)-alkyl, xe2x80x94(CH2)mxe2x80x94OR11, xe2x80x94(CH2)pxe2x80x94(C3-C6)-cycloalkyl and R11 is selected from the group consisting of hydrogen and (C1-C7)-alkyl, xe2x80x94(CH2)mxe2x80x94NHxe2x80x94C(O)Oxe2x80x94(C1-C7)-alkyl and xe2x80x94(CH2)p-pyridyl;
R3 is selected from the group consisting of hydrogen and fluoro;
R6 is selected from the group consisting of halogen, (C1-C7)-alkoxy, (C1-C7)-alkylthio, xe2x80x94Oxe2x80x94(CH2)mxe2x80x94OR11, xe2x80x94O-fluoro-(C1-C7)-alkyl and xe2x80x94NHR12;
R9 is hydrogen; and
R12 is selected from the group consisting of (C1-C7)-alkyl, xe2x80x94(CH2)mxe2x80x94OR and xe2x80x94(CH2)pxe2x80x94(C3-C6)-cycloalkyl.
Exemplary preferred compounds of formula Ib2 are selected from the group consisting of 2-(cyclopropylmethyl-amino)-4-(2-hydroxy-ethylamino)-6-(4-phenyl-piperidin-1-yl)-pyrimidine-5-carbonitrile, 4-(4-phenyl-piperidin-1-yl)-2-[(pyridin-3-ylmethyl)-amino]-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile, 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-[(pyridin-3-ylmethyl)-amino]-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile, 2-caclopropylamino-4-(2-hydroxy-ethylamino)-6-(4-phenyl-piperidin-1-yl)-pyrimidine-5-carbonitrile, 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-(2-hydroxy-ethylamino)-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile, 2-(cyclopropylmethyl-amino)-4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile, 4-(2-hydroxy-ethylamino)-6-(4-phenyl-piperidin-1-yl)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidioine-5-carbonitrile, and 2-(2-hydroxy-ethylamino)-4-(4-phenyl-piperidin-1-yl)-6-(2,2,2-trifluoro-ethoxy)-pyrimidine-5-carbonitrile.
Another preferred compound of formula I in the scope of the present invention is a compound of formula 
or a pharmaceutically acceptable salt thereof
A preferred compound of formula Ic has the formula 
wherein
R2 is selected from the group consisting of (C1-C7)-alkyl andxe2x80x94NHR10,
R10 is selected from the group consisting of (C1-C7)-alkyl, xe2x80x94(CH2)mxe2x80x94OR11, -(CH2)pxe2x80x94(C3-C6)-cycloalkyl and R11 is selected from the group consisting of hydrogen and (C1-C7)-alkyl;
R3 is selected from the group consisting of hydrogen and fluoro; and
R7 is selected from the group consisting of (C1-C7)-alkyl and phenyl.
A more preferred compound of formula Ic1 is, wherein R2 is (C1-C7)-alkyl and R3 is hydrogen. A more preferred compound exemplary of a formula Ic1 is selected from the group consisting of 4-(4-fluoro-phenyl)-6xe2x80x2-methyl-5xe2x80x2-phenyl-3,4,5,6-tetrahydro-2H-[1,2xe2x80x2]bipyrazinyl-3xe2x80x2-carbonitrile, 5xe2x80x2-ethyl-4-(4-fluoro-phenyl)-6xe2x80x2-methyl-3,4,5,6-tetrahydro-2H-[1,2xe2x80x2]bipyrazinyl-3xe2x80x2-carbonitrile, 6xe2x80x2-ethyl-4-(4-fluoro-phenyl)-5xe2x80x2-methyl-3,4,5,6-tetrahydro-2H-[1,2xe2x80x2]bipyrazinyl-3xe2x80x2-carbonitrile, 5xe2x80x2-ethyl-6xe2x80x2-methyl-4-phenyl-3,4,5,6-tetrahydro-2H-[1,2xe2x80x2]bipyrazinyl-3xe2x80x2-carbonitrile, and 6xe2x80x2-ethyl-5xe2x80x2-methyl-4-phenyl-3,4,5,6-tetrahydro-2H-[1,2xe2x80x2]bipyrazinyl-3xe2x80x2-carbonitrile.
Another preferred compound of formula Ic has the formula 
A more preferred compound of formula Ic2 is wherein R2 is (C1-C7)-alkyl and R3 is hydrogen.
An exemplary more preferred compound of formula Ic2 is selected from the group consisting of 6-ethyl-5-methyl-3-(4-phenyl-piperidin-1-yl)-pyrazine-2-carbonitrile and 5-ethyl-6-methyl-3-(4-phenyl-piperidin-1-yl)-pyrazine-2-carbonitrile.
Another preferred compound of formula I has the formula 
A more preferred compound of formula Ic3 is wherein R2 is selected from the group consisting of (C1-C7)-alkyl and xe2x80x94NHR10, wherein R10 is selected from the group consisting of (C1-C7)-alkyl, xe2x80x94(CH2)mxe2x80x94OR11, xe2x80x94(CH2)pxe2x80x94(C3-C6)-cycloalkyl, and R11 is selected from the group consisting of hydrogen and (C1-C7)-alkyl;
R3 is selected from the group consisting of hydrogen and fluoro; and
R7 is selected from the group consisting of (C1-C7)-alkyl and phenyl.
A further preferred compound of formula Ic3 is seen when R2 is (C1-C7)-alkyl and R3 is hydrogen.
An exemplary further preferred compound of formula Ic3 is selected from the group consisting of 6-ethyl-5-methyl-3-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-pyrazine-2-carbonitrile and 5-ethyl-6-methyl-3-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-pyrazine-2-carbonitrile.
Yet another preferred compound of formula I in the scope of the invention has the formula 
or a pharmaceutically acceptable salt thereof.
A more preferred compound of formula Id has the formula 
wherein R2 is selected from the group consisting of (C1-C7)-alkyl and fluoro; and R8 is (C1-C7)-alkyl.
Exemplary of a preferred compound of formula Id1 is a compound selected from the group consisting of 5xe2x80x2-ethyl-4-(4-fluoro-phenyl)-6xe2x80x2-methyl-4xe2x80x2-oxy-3,4,5,6-tetrahydro-2H-[1,2xe2x80x2]bipyrazinyl-3xe2x80x2-carbonitrile, and 6xe2x80x2-ethyl-4-(4-fluoro-phenyl)-5xe2x80x2-methyl-4xe2x80x2-oxy-3,4,5,6-tetrahydro-2H-[1,2xe2x80x2]bipyrazinyl-3xe2x80x2-carbonitrile.
Also preferred is another compound of formula I having the formula 
or a pharmaceutically acceptable salt thereof.
A more preferred compound of formula 1e has the formula 
wherein R2 is xe2x80x94NHR10, wherein R10 is selected from the group consisting of (C1-C7)-alkyl, xe2x80x94(CH2)mxe2x80x94OR11, xe2x80x94(CH2)pxe2x80x94(C3-C6)-cycloalkyl, and R11 is selected from the group consisting of hydrogen and (C1-C7)-alkyl; and R3 is hydrogen. An exemplary compound of formula Ie1 is 3-(2-hydroxy-ethylamino)-5-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-[1,2,4]triazine-6-carbonitrile.
The term xe2x80x9c(C1-C7)-alkylxe2x80x9d (xe2x80x9clower alkylxe2x80x9d) used in the present description denotes straight-chain or branched saturated hydrocarbon residues with 1-7 carbon atoms, preferably with 1-4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, butyl and the like.
The term xe2x80x9c(C2-C7)-alkenylxe2x80x9d (xe2x80x9clower alkenylxe2x80x9d) used in the present description denotes straight-chain or branched unsaturated hydrocarbon residues with 2-7 carbon atoms, preferably with 2-4 carbon atoms. A xe2x80x9c(C2-C7)-alkenylxe2x80x9d group includes, for example, vinyl, prop-2-enyl, but-3-enyl, pent-4-enyl and isopropenyl.
The term xe2x80x9c(C3-C6)-cycloalkylxe2x80x9d denotes a saturated carbocyclic group containing from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The term xe2x80x9chalogenxe2x80x9d embraces fluorine, chlorine, bromine and iodine.
A xe2x80x9cfluoro-(C1-C7)-alkylxe2x80x9d group is a lower alkyl group as defined above, which is substituted by one or more fluorine atoms, for example trifluoromethyl, 2-fluoroethyl or 2,2,2-trifluoroethyl.
The terms xe2x80x9c(C1-C7)-alkoxyxe2x80x9d or xe2x80x9c(C1-C7)-alkylthioxe2x80x9d denote an lower alkyl group linked to an oxygen or sulphur atom, respectively, wherein the lower alkyl is defined as above. A (C1-C7)-alkoxy or a (C1-C7)-alkylthio group includes for example methoxy, ethoxy, methylthio or ethylthio.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to any salt derived from a pharmaceutically acceptable inorganic or organic acid or base.
The compounds of formula I and their pharmaceutically acceptable salts can be manufactured by
reacting a compound of formula 
wherein R13 is halogen, with a compound of formula 
forming a compound of formula 
wherein R1 to R5 and Z are as defined above,
and, if desired, converting a compound of formula Ia into a pharmaceutically acceptable salt; or
reacting a compound of formula 
wherein R6 and R13 are halogen, with a compound of formula 
and, if desired, substituting the halogen of R6 with the respective nucleophiles forming a compound of formula 
wherein R1 to R4, R6 and Z are as defined above,
and, if desired, converting a compound of formula Ib into a pharmaceutically acceptable salt; or
reacting a compound of formula 
wherein R13 is halogen, with a compound of formula 
forming a compound of formula 
wherein R1 to R4, R7 and Z are as defined above,
and, if desired, converting a compound of formula Ic into a pharmaceutically acceptable salt; or
reacting a compound of formula 
wherein R13 is halogen, with a compound of formula 
forming a compound of formula 
wherein R1 to R4, R8 and Z are as defined above,
and, if desired, converting a compound of formula Id into a pharmaceutically acceptable salt; or
reacting a compound of formula 
wherein R13 is halogen, with a compound of formula 
and substituting the thiomethyl group with the respective nucleophiles to obtain a compound of formula 
wherein R21 is xe2x80x94NHR10 and R1, R3, R4 and Z are as defined above,
and, if desired, converting a compound of formula Ie-1 into a pharmaceutically acceptable salt; or
reacting a compound of formula 
wherein R22 is (C1-C7)-alkyl and R13 is halogen, with a compound of formula 
forming a compound of formula 
wherein R22 is (C1-C7)-alkyl and R1, R3, R4 and Z are as defined above, and, if desired, converting a compound of formula Ie into a pharmaceutically acceptable salt.
Compounds of formula Ia and Ib, wherein R2 is (C1-C7)-alkyl, can be manufactured by reacting alkyl 6-bromo- or 6-chloro-5-nitro-3H-pyrimidin-4-ones of formula IIa-1, e.g. 6-bromo-2-methyl-5-nitro-3H-pyrimidin-4-one [Eur. Pat. Appl. EP 1 074 549 A2 (2001)], with optionally substituted phenyl-piperazines, phenyl-tetrahydropyridines or phenylpiperidines of formula III in the presence of a base like potassium carbonate, triethylamine or ethyl-diisopropylamine in solvents like N,N-dimethylformamide, dimethylsulfoxide, acetone, methyl-ethylketone or tetrahydrofurane at temperatures between 0xc2x0 C. and 100xc2x0 C. to the pyrimidinones IV (Scheme 1). Alkylation of the pyrimidinones IV using optionally substituted alkyl halides, tosylates, mesylates or trifluoro-methansulfonates in solvents like ethanol, methanol, dichloromethane, chloroform, N,N-dimethylformamide, dimethylsulfoxide, acetone, methyl-ethylketone or tetrahydrofurane in the presence of base like alkali carbonates, e.g. sodium, potassium or cesium carbonate, tertiary amines like triethylamine or ethyl-diisopropylamine, alkali metal hydrides, like sodium or potassium hydride, or phase transfer catalysts like benzyltrimethylammonium chloride in the presence of solid or concentrated aqueous sodium hydroxide gives variable mixtures of N- and/or O-alkylated compounds Ia-1 and Ib-1 wherein R14 signifies (C1-C7)-alkyl, xe2x80x94(CH2)mxe2x80x94OR11l, or fluoro-(C1-C7)-alkyl. The compounds Ia-1 and Ib-1 may contain functional groups in protected form in the N- or O-alkyl function which allow further structural modifications after removal of the protective functions. 
Known bis(methylthio)-acrylates V react with optionally substituted phenylpiperazines, phenyl-tetrahydropyridine or phenylpiperidines of formula III in the presence of bases like potassium carbonate and/or triethylamine in solvents like ethanol, methanol, acetone or methyl-ethylketone at temperatures between room temperature and 100xc2x0 C. to adducts VI, which can be formed as the Z-isomer, as mixture of the E- and Z-isomers or as the E-isomer [Scheme 2 and Eur. Pat. Appl. EP 1 074 549 A2 (2001)]. The terms xe2x80x9cExe2x80x9d and xe2x80x9cZxe2x80x9d used in this context are xe2x80x9centgegenxe2x80x9d and xe2x80x9czusammenxe2x80x9d: this useage is unrelated to the xe2x80x9cZxe2x80x9d of formula I. Thereupon, adducts VI can be reacted with amidines or urea derivatives of formula VII or VIII either in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene in N,N-dimethylformamide or dimethylsulfoxide at temperatures between 70xc2x0 C. and 140xc2x0 C. or in the presence of sodium ethylate in ethanol preferentially at reflux thus yielding pyrimidinones Ia-2 or substituted pyrimidinones Ia-3. Pyrimidinones Ia-2 can then be alkylated as described for the sequence IV= greater than Ia-1 and Ib-1 in Scheme I. 
If an allyl moiety is introduced as R5, then, it can also serve as protective function.
Thus, it allows modification at other parts of the molecules, e.g. in R2 and a later removal of the N-allyl function by lithium borohydride in the presence of palladium(II)acetate and triphenylphosphin in an inert solvent like tetrahydrofuran or 1,2-dimethoxyethane at temperatures between room temperature and 60xc2x0 C.
Compounds of formula Ib can be obtained by sequential substitution of compounds of formula IIb with the respective nucleophiles. The nucleophilic substitution reactions can be performed according to known methods, and for the sequence of introduction, the presence of further functionalities in the nucleophile has to be taken into account, a fact generally known to persons skilled in the art. For example, treatment of compounds of formula IIb-1 with compounds of formula III via compounds of formula IX are leading to compounds of formula Ib. Selective monosubstituion of di-chloro pyrimidines IIb-1 (Scheme 3) with optionally substituted secondary amines III can be performed in solvents like N,N-dimethylform-amide or dimethylsulfoxide in the presence of a base like triethylamine at temperatures between 0xc2x0 C. and 60xc2x0 C. producing mono-chloro pyrimidines IX. Thereafter, the remaining chloro atom in compounds IX can be replaced by i) alkoxy functions, treating compounds of formula IX with an alcoholate in the corresponding alcohol as solvent or in an inert solvent like tetrahydrofurane, N,N-dimethylformamide or dimethylsulfoxide at temperatures between room temperature and 100xc2x0 C.; or by ii) amino functions, treating compounds of formula IX with an amine in an inert solvent like tetrahydrofurane, N,N-dimethylformamide or dimethylsulfoxide at temperatures between room temperature and 100xc2x0 C.; or by iii) thio functions, treating compounds of formula IX with a thiol in the presence of a base like triethylamine or sodium hydride in an alcohol, N,N-dimethylform-amide or dimethylsulfoxide at temperatures between room temperature and 100xc2x0 C. The replacement of the chloro group by a hydroxy function is preferentially performed in a two step procedure: a 4-methoxy-benzyloxy function is introduced first by reacting IX with the corresponding alcoholate as described above followed by treatment with methanolic hydrogen chloride at temperatures between 0xc2x0 C. and 50xc2x0 C. In case of hydroxy group containing intermediates, these can be protected according to known methods before the treatment with the alcoholates. 
Compounds of formula IIb-1 wherein R2 signifies xe2x80x94NHR10 can be obtained starting from the 4,6-dichloro-2-methylsulfanyl-pyrimidine derivative X or the 2,4,6-trichloro-pyrimidine derivative XI. Starting with compounds of formula X, they are transformed into the 2-methylsulphonyl derivative according to known oxidative methods, e.g. by 3-chloro-perbenzoic acid in dichloromethane, followed by the treatment with the respective amines in tetrahydrofurane, dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide or dimethylsulfoxide at temperatures between room temperature and about 100xc2x0 C. to yield compounds of formula IIb-1.
In case, compounds of formula XI are selected as starting materials, the treatment with amines in tetrahydrofurane, dioxane, 1,2-dimethoxyethane, ethanol, N,N-dimethyl-formamide or dimethylsulfoxide, at temperatures between room temperature and about 100xc2x0 C., in presence of a base, e.g. potassium carbonate, triethylamine or ethyl-diisopropyl-amine yields the 2- and 4-substituted derivatives. These can be separated by chromato-graphic methods and identified by physical methods known as such like 13C-NMR or X-ray analysis; e.g. when R2 signifies hydroxyethylamino the assignment was performed by X-ray analysis. When an excess of the nucleophile is used under the aforementioned conditions, the 2,4-disubstituted derivative can be obtained.
To obtain compounds of formula Ic, 1,2-dicarbonyl compounds XII with R2 and R7 signifying both independently from each other hydrogen, phenyl, (C1-C7)-alkyl or (C2-C7)-alkenyl, react with 2-amino-malonic acid diamide XIII as described in J. Amer. Chem. Soc. 1949, 71, 78-81, either in the presence of an aqueous base at temperatures between 0xc2x0 C. and 60xc2x0 C. or in the absence of a base in solvents like water or an alcohol at temperatures between room temperature and 120xc2x0 C. to form the 3-oxo-3,4-dihydro-pyrazine-2-carboxylic acid amides XIVa and XIVb, in which the former substituent R2 of the 1,2-dicarbonyl compounds XII became the substituent R7xe2x80x2 and the former substituent R7 in the 1,2-dicarbonyl compounds XII became the substituent R2xe2x80x2. Treatment of XIVa and XIVb either separately or as a mixture with phosphorus oxychloride and optionally additional phosphorus pentachloride in the presence of triethylamine or diethylaniline at temperatures between 40xc2x0 C. and 120xc2x0 C. give 3-chloro-pyrazine-2-carbonitriles XVa and XVb (Scheme 4).
3-chloro-pyrazine-2-carbonitriles XVa and XVb react either separately or as a mixture with optionally substituted phenyl-piperazines, phenyl-tetrahydropyridines or phenyl-piperidines or their hydrochlorides in solvents like N,N-dimethylformamide, acetonitrile, acetone or dimethylsulfoxide in the presence of a base like potassium carbonate or a tertiary amine as diisopropyl-ethylamine at temperatures between room temperature and 80xc2x0 C. to form the desired 3-(phenyl-piperazine-yl, phenyl-tetrahydro-pyridine-yl or phenylpiperidine-yl)-pyrazine-2-carbonitriles Ic-1 and Ic-2 which can be separated by known methods such as chromatography or crystallization. 
To obtain compounds of formula Id, 3-chloro-pyrazine-2-carbonitriles XVc and XVd can be oxidized to the corresponding mono-oxy-pyrazine compounds by various methods. If hydrogen peroxide in a solvent like trifluoroacetic acid is used preferentially at temperatures between 0xc2x0 C. and 60xc2x0 C., then mainly l-oxy-pyrazine-2-carbonitriles IId-1 and IId-2 are formed (Scheme 5). 1-Oxy-pyrazine-2-carbonitriles IId-1 and IId-2 react either separately or as a mixture with optionally substituted phenyl-piperazines, phenyl-tetrahydropyridines or phenylpiperidines or their hydrochlorides in solvents like N,N-dimethylformamide, acetonitrile, acetone or dimethylsulfoxide in the presence of a base like potassium carbonate or a tertiary amine as diisopropyl-ethylamine at temperatures between room temperature and 80xc2x0 C. to form the desired 3-(phenyl-piperazine-yl, phenyl-tetrahydropyridine-yl or phenylpiperidine-yl) 1-oxy-pyrazine-2-carbonitriles Id-1 and Id-2 which can be separated by known methods such as chromatography or crystallization. 
The diazotization of the 3-amino-5-chloro-2-cyano-pyrazine XVI according to J.Org.Chem. 1975, 40, 2341-2347, with t-butyl-nitrite in solvents like acetonitrile or N,N-dimethylformamide in the presence of copper-(II)-bromide at temperatures between room temperature and 95xc2x0 C. gives the 3-bromo-5-chloro-2-cyano-pyrazine IIg. The 3-bromo-5-chloro-2-cyano-pyrazine IIg reacts with one equivalent of a primary or secondary amine to two products, in which either the chloro-atom or the bromo-atom is replaced in the amine moiety. If the reaction is performed with a primary amine R10NH2 in a solvent like dioxane or tetrahydrofurane in the presence of a base like triethylamine or diisopropylethylamine, preferentially at room temperature, then the pyrazine IIh with replaced chloro-atom can be obtained with reasonable selectivity. In a second analogous reaction, optionally substituted phenyl-piperazines, phenyl-tetrahydro-pyridines or phenylpiperidines or their hydrochlorides can then be reacted with the pyrazine IIh in solvents like N,N-dimethylformamide, tetrahydrofurane, dioxane, acetonitrile, acetone or dimethylsulfoxide and in the presence of a base like potassium carbonate or a tertiary amine like diisopropyl-ethylamine at temperatures between room temperature and 80xc2x0 C. giving compounds of formula Ic-3 wherein R7 signifies hydrogen (Scheme 6). 
Compounds of formula Ie-1a 
wherein R21 signifies xe2x80x94NHR10 , can be obtained by reacting compounds of formula Ie-3.
with appropriate nucleophiles. Substitution of the Me-S-group in compound Ie-3 by optionally substituted N-nucleophiles can be performed in water, ethanol, N,N-dimethylformamide, dimethylsulfoxide, 1,2-dimethoxyethane, preferentially in dioxane at elevated temperatures, preferentially 100xc2x0 C. to 160xc2x0 C.
Compounds of formula Ie-3 are prepared by reaction of 1, 3-(methylthio)-5-chloro-6-cyano-1,2,4-triazine (J. J. Huang, J. Org. Chem. 1985, 50, 2293-2298) with amines of formula III 
in the presence of a base like triethylamine or ethyl-diisopropylamine in solvents like N,N-dimethylformamide, dimethylsulfoxide, methyl-ethylketone, ethanol, dioxane or tetrahydrofuran at temperatures between 10xc2x0 C. and 50xc2x0 C.
The functionalization of the N-nucleophiles can also serve as a protective function. Thus, modifications at the other part of the R21-substituent are allowed, e.g. removal of a N-protecting group, like the tert-butoxycarbonyl group, by methods well documented in the literature.
Compounds of formula Ie-2a 
wherein R22 signifies (C1-C7)-alkyl can be prepared by reacting the intermediate IIf-1 with amines of formula III in the presence of a base like triethylamine or ethyl-diisopropylamine in solvents like N,N-dimethylformamide, dimethylsulfoxide, methyl-ethylketone, ethanol, dioxane or tetrahydrofurane at temperatures between 10xc2x0 C. and 50xc2x0 C.
The intermediate If-1 can be synthesized in analogy to the procedure described in J. Org. Chem. 1972, 37 (24), 3958-3960, starting with the condensation of the corresponding amidrazones XVII and methyl or ethyl oxomalonate XVIII, followed by ammonolysis of the ester XIX, and, finally, dehydration of the amide XX and substitution of the hydroxy group by chlorine (Scheme 7). 
The pharmaceutically acceptable salts can be manufactured readily according to methods known per se and taking into consideration the nature of the compound to be converted into a salt. Inorganic or organic acids such as, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like are suitable for the formation of pharmaceutically acceptable salts of basic compounds of formula I. Compounds which contain the alkali metals or alkaline earth metals, for example sodium, potassium, calcium, magnesium or the like, basic amines or basic amino acids are suitable for the formation of pharmaceutically acceptable salts of acidic compounds of formula I.
The compounds of formula I and their pharmaceutically acceptable salts are, as already mentioned above, metabotropic glutamate receptor antagonists and can be used for the treatment or prevention of acute and/or chronic neurological disorders, such as epilepsy, stroke, chronic and acute pain, psychosis, schizophrenia, Alzheimer""s disease, cognitive disorders, memory deficits and psychosis. Other treatable indications are restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Further treatable indications are Huntington""s chorea, ALS, dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficient functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, dyskinesia and depression.
The compounds of the present invention are group I mGluR antagonists. Their pharmacological activity was tested using the following method:
Binding Assay for the Characterization of mGluR 1 Antagonistic Properties
Binding assay with tritiated 1-ethyl-2-methyl-6-oxo-4-(1,1,2-tritritio-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,6-dihydro-pyrimidine-5-carbonitrile: HEK 293 cells were transiently transfected with the rat mGluR1 a receptor. The cells were collected and washed 3 times with PBS. The cell pellets were frozen at xe2x88x9280xc2x0 C. Membranes were prepared from HEK 293 cells transfected with the rat mGluR1 a receptor and used in the binding experiments at 10 xcexcg proteins per assay after resuspension in a HEPES NaOH 20 mM, pH=7.4 binding buffer. 1-Ethyl-2-methyl-6-oxo-4-(1,1,2-tritritio-1,2,4,5-tetrahydro-benzo [d]azepin-3-yl)-1,6-dihydro-pyrimidine-5-carbonitrile (S.A 33.4 Ci/mmol) was used at 3 nM final concentration. The incubation with variable concentrations of potential inhibitors was performed for 1 hour at room temperature, the incubate was then filtered onto GF/B glass fiber filter preincubated 1 hour in PEI 0,1% and washed 3 times with 1 ml of cold binding buffer. The radioactivity retained on the unifilter 96 was counted using a Topcount xcex2 counter. After correction for non specific binding the data were normalized and the IC50 value calculated using a 4 parameters logistic equation which was fitted to the inhibition curve.
The preferred compounds have an IC50 range of 0.001-10.0 xcexcmol/l.
In table I below are shown some specific IC50 values of preferred compounds of formula I of the present invention as measured with the binding assay described above:
The compounds of formula I and pharmaceutically acceptable salts thereof can be used as pharmaceutical compositions, e.g. in the form of pharmaceutical preparations. The pharmaceutical compositions can be administered orally, e.g. in the form of tablets, coated tablets, dragxc3xa9{acute over ( )}es, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula I and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical compositions. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, draxc3xa9es and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Adjuvants, such as alcohols, polyols, glycerol, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of formula I, but as a rule are not necessary.
Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
In addition, the pharmaceutical compositions can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
As mentioned earlier, pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert excipient are also an object of the present invention, as is a process for the production of such pharmaceutical compositions which comprises bringing a therapeutically effective amount of one or more compounds of formula I or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical dosage form together with one or more therapeutically inert carriers.
The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, the effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day being preferred for all of the indications described. The daily dosage for an adult human being weighing 70 kg accordingly lies between 0.7-1400 mg per day, preferably between 7 and 700 mg per day.
Finally, as mentioned earlier, compounds of formula I and of pharmaceutically acceptable salts are useful thereof for the production of pharmaceutical compositons. These pharmaceutical compositions are useful in a method of treatment for the control or prevention of acute and/or chronic neurological disorders which comprises administering a therapeutically effective amount of the pharmaceutical composition containing the compound of formula 1 or a pharmaceutically acceptable salt there eo to a person having a disease responsive to mediation of the mGluR1 receptor
The following examples are provided for illustration of the invention. They should not be considered as limiting the scope of the invention, but merely as being representative thereof. Unless stated to the contrary, all of the examples listed below were prepared and characterized as described.